Sue R. Downie

Ventilation heterogeneity is a major determinant of airway hyperresponsiveness in asthma, independent of airway inflammation

Background: Airway hyperresponsiveness is the ability of airways to narrow excessively in response to inhaled stimuli and is a key feature of asthma. Airway inflammation and ventilation heterogeneity have been separately shown to be associated with airway hyperresponsiveness. A study was undertaken to establish whether ventilation heterogeneity is associated with airway hyperresponsiveness independently of airway inflammation in subjects with asthma and to determine the effect of inhaled corticosteroids on this relationship. Methods: Airway inflammation was measured in 40 subjects with asthma by exhaled nitric oxide, ventilation heterogeneity by multiple breath nitrogen washout and airway hyperresponsiveness by methacholine challenge. In 18 of these subjects with uncontrolled symptoms, measurements were repeated after 3 months of treatment with inhaled beclomethasone dipropionate. Results: At baseline, airway hyperresponsiveness was independently predicted by airway inflammation (partial r2 = 0.20, p<0.001) and ventilation heterogeneity (partial r2 = 0.39, p<0.001). Inhaled corticosteroid treatment decreased airway inflammation (p = 0.002), ventilation heterogeneity (p = 0.009) and airway hyperresponsiveness (p<0.001). After treatment, ventilation heterogeneity was the sole predictor of airway hyperresponsiveness (r2 = 0.64, p<0.001). Conclusions: Baseline ventilation heterogeneity is a strong predictor of airway hyperresponsiveness, independent of airway inflammation in subjects with asthma. Its persistent relationship with airway hyperresponsiveness following anti-inflammatory treatment suggests that it is an important independent determinant of airway hyperresponsiveness. Normalisation of ventilation heterogeneity is therefore a potential goal of treatment that may lead to improved long-term outcomes.

Exhaled nitric oxide levels in atopic children: relation to specific allergic sensitisation, AHR, and respiratory symptoms

Background: Exhaled nitric oxide (eNO), which has been proposed as a measure of airway inflammation, is increased in atopic subjects. This raises the question of whether eNO provides any additional information about airway inflammation in asthmatic subjects, other than as a marker for atopy. A study was undertaken to determine whether eNO levels in a population of atopic children are associated with sensitisation or natural exposure to specific allergens, and to examine the relationship between eNO, airway responsiveness, and current respiratory symptoms. Methods: Exhaled NO and airway responsiveness to histamine were measured in winter and in summer in 235 children aged 8–14 years who had been classified as atopic by skin prick testing. Current respiratory symptoms, defined as wheeze or cough during the month preceding the test, were measured by a parent completed questionnaire. Airway hyperresponsiveness (AHR) was defined as a dose response ratio (DRR) of >8.1 (% fall in forced expiratory volume in 1 second (FEV1)/μmol + 3). Results: Sensitisation to house dust mite was associated with raised eNO levels in winter while sensitisation to Cladosporium was associated with raised eNO levels in both winter and summer. Grass pollen sensitisation was not associated with raised eNO levels in either season. Exhaled NO correlated significantly with DRR histamine (r=0.43, p<0.001) independently of whether the children had current symptoms or not. In children with current wheeze, those with AHR had eNO levels 1.53 (95% CI 1.41 to 1.66) times higher than those without AHR (p=0.006). Neither DRR (p=1.0) nor eNO levels (p=0.92) differed significantly between children with or without persistent dry cough in the absence of wheeze. Conclusions: In atopic children, raised eNO levels are associated with sensitisation to perennial allergens, but not to seasonal allergens such as grass pollen. In this population, an increase in eNO is associated with AHR and current wheezing, suggesting that eNO is more than just a marker for atopy.

Obesity is a determinant of asthma control independent of inflammation and lung mechanics

BACKGROUND It is unclear why obesity is associated with worse asthma control. We hypothesized that (1) obesity affects asthma control independent of spirometry, airway inflammation, and airway hyperresponsiveness (AHR) and (2) residual symptoms after resolution of inflammation are due to obesity-related changes in lung mechanics. METHODS Forty-nine subjects with asthma underwent the following tests, before and after 3 months of high-dose inhaled corticosteroid (ICS) treatment: five-item asthma control questionnaire (ACQ-5), spirometry, fraction of exhaled nitric oxide (Feno), methacholine challenge, and the forced oscillation technique, which allows for the calculation of respiratory system resistance (Rrs) and respiratory system reactance (Xrs) as indicators of airway caliber and elastic load, respectively. The effects of treatment were assessed by BMI group (18.5-24.9, 25-29.9, and ≥ 30 kg/m²) using analysis of variance. Multiple regression analyses determined the independent predictors of ACQ-5 results. RESULTS At baseline, the independent predictors of ACQ-5 results were FEV(1), Feno, and BMI (model r² = 0.38, P < .001). After treatment, asthma control, spirometry, airway inflammation, and AHR improved similarly across BMI groups. The independent predictors of ACQ-5 results after treatment were Rrs and BMI (model r² = 0.42, P < .001). CONCLUSIONS BMI is a determinant of asthma control independent of airway inflammation, lung function, and AHR. After ICS treatment, BMI again predicts ACQ-5 results, but independent of obesity-related changes in lung mechanics.

Effects of methacholine on small airway function measured by forced oscillation technique and multiple breath nitrogen washout in normal subjects

The multiple breath nitrogen washout (MBNW) can be analysed to produce the parameters Scond and Sacin as measures of ventilation heterogeneity in conductive and acinar airways, respectively. The derivation of these parameters is based on a model of pulmonary ventilation and results of similar modelling suggest that respiratory system conductance (Grs) measured by forced oscillation technique (FOT) is also sensitive to heterogeneity and to airway closure. Therefore, Scond, the volume of gas trapping at FRC (VtrappedFRC) and Grs may be inter-related parameters. These relationships were examined in 12 normals under baseline and bronchoconstricted states. Specific Grs was measured at 5Hz (sGrs5=Grs5/FRC) and Scond, Sacin and VtrappedFRC by MBNW, before and after methacholine challenge. Scond was independently predicted by VtrappedFRC and FRC in a multivariate model (R2=0.68, p=0.002). Post methacholine challenge, Scond related only to VtrappedFRC (R2=0.79, p<0.0001). The absolute change in Scond induced by methacholine challenge were predicted by the changes in VtrappedFRC and sGrs5 in a multivariate model (R2=0.82, p=0.0002). Sacin was unrelated to VtrappedFRC and sGrs5 before and after methacholine challenge. In conclusion, Scond and sGrs5 are measurements that are sensitive to changes occurring to the function of peripheral conducting airways, in particular heterogeneity and airway closure, while Sacin and presumably heterogeneity in terminal airways, are independent of these. Scond is also related to lung size. We review the current state of knowledge of FOT and MBNW in obstructive lung diseases and discuss future research directions.

Association between nasal and bronchial symptoms in subjects with persistent allergic rhinitis

Background:  The association between nasal and bronchial symptoms, and the course of bronchial responsiveness and airway inflammation in house dust mite sensitive persistent rhinitis over a prolonged time period has not been thoroughly explored.

Predictors of airway hyperresponsiveness differ between old and young patients with asthma

BACKGROUND Age-related increases in morbidity and mortality due to asthma may be due to changes in pathophysiology as patients with asthma get older. There is limited knowledge about the effects of age on the predictors of airway hyperresponsiveness (AHR), a key feature of asthma. The aim of this study was to determine if the pathophysiologic predictors of AHR, including inflammation, ventilation heterogeneity, and airway closure, differed between young and old patients with asthma. METHODS Sixty-one young (18-46 years) and 43 old (50-80 years) patients with asthma had lung function, lung volumes, fraction of exhaled nitric oxide, ventilation heterogeneity, and airway responsiveness to methacholine measured. Airway response to methacholine was measured by the dose-response slope, as the percent fall in FEV(1) per micromole of methacholine. Indices of ventilation heterogeneity were calculated for convection-dependent and diffusion-dependent airways. RESULTS In young patients with asthma, the independent predictors of AHR were convection-dependent ventilation heterogeneity, exhaled nitric oxide, and % predicted FEV(1)/FVC (model r(2) = 0.51, P < .0001). In old patients with asthma, the independent predictors of airway responsiveness were % predicted residual volume, diffusion-dependent ventilation heterogeneity, and % predicted FEV(1) (model r(2) = 0.57, P < .0001). CONCLUSIONS In old patients with asthma, AHR is predicted by gas trapping and ventilation heterogeneity in peripheral, diffusion-dependent airways. In the young, it is predicted by ventilation heterogeneity in less peripheral conducting airways and by inflammation. These findings suggest that there are differences in the pathophysiologic determinants of AHR between young and old patients with asthma.

Effect of methacholine on peripheral lung mechanics and ventilation heterogeneity in asthma

The forced oscillation technique (FOT) and multiple-breath nitrogen washout (MBNW) are noninvasive tests that are potentially sensitive to peripheral airways, with MBNW indexes being especially sensitive to heterogeneous changes in ventilation. The objective was to study methacholine-induced changes in the lung periphery of asthmatic patients and determine how changes in FOT variables of respiratory system reactance (Xrs) and resistance (Rrs) and frequency dependence of resistance (Rrs5-Rrs19) can be linked to changes in ventilation heterogeneity. The contributions of air trapping and airway closure, as extreme forms of heterogeneity, were also investigated. Xrs5, Rrs5, Rrs19, Rrs5-Rrs19, and inspiratory capacity (IC) were calculated from the FOT. Ventilation heterogeneity in acinar and conducting airways, and trapped gas (percent volume of trapped gas at functional residual capacity/vital capacity), were calculated from the MBNW. Measurements were repeated following methacholine. Methacholine-induced airway closure (percent change in forced vital capacity) and hyperinflation (change in IC) were also recorded. In 40 mild to moderate asthmatic patients, increase in Xrs5 after methacholine was predicted by increases in ventilation heterogeneity in acinar airways and forced vital capacity (r(2) = 0.37, P < 0.001), but had no correlation with ventilation heterogeneity in conducting airway increase or IC decrease. Increases in Rrs5 and Rrs5-Rrs19 after methacholine were not correlated with increases in ventilation heterogeneity, trapped gas, hyperinflation, or airway closure. Increased reactance in asthmatic patients after methacholine was indicative of heterogeneous changes in the lung periphery and airway closure. By contrast, increases in resistance and frequency dependence of resistance were not related to ventilation heterogeneity or airway closure and were more indicative of changes in central airway caliber than of heterogeneity.

Symptoms of persistent allergic rhinitis during a full calendar year in house dust mite-sensitive subjects

Background:  Little is known about the natural course of persistent rhinitis symptoms over a prolonged period.

Sleep disturbance in persistent allergic rhinitis measured using actigraphy

BACKGROUND Tiredness, fatigue, and impaired quality of life are common in patients with persistent allergic rhinitis (PAR). These symptoms may also be associated with reduced sleep quality in individuals with rhinitis. OBJECTIVE To determine whether sleep disturbance can be detected using actigraphy in patients with PAR. METHODS Ten house dust mite-allergic rhinitic patients and 10 nonallergic nonrhinitic control subjects were studied for 5 consecutive days and night. Continuous activity monitoring during the study period using actigraphy was used to obtain markers of sleep quality, such as sleep onset, sleep duration, and sleep fragmentation. In addition, participants recorded in a sleep diary the time they went to bed, the time they went to sleep, the time they awoke, and the quality of their sleep. RESULTS Allergic rhinitic patients were found to have an increased fragmentation index value, indicative of reduced sleep quality and increased sleep disturbance, compared with the control group (P = .007). CONCLUSIONS Using actigraphy, we identified specific sleep disturbances in patients with PAR that may result in the increased tiredness, fatigue, and impaired quality of life typically experienced in such patients.

A comparison of two methods for measuring airway distensibility: nitrogen washout and the forced oscillation technique.

The measurement of airway stiffness is an important tool for studying airway remodelling in asthma. The relationship between airway calibre and lung volume (airway distensibility) was measured by forced oscillation technique (FOT) and compared with that measured by single-breath nitrogen washout (SBNW). In four non-asthmatic healthy subjects and three asthmatics, anatomical dead space (VDF) was measured by SBNW and respiratory system conductance (Grs) was measured by FOT at 6 Hz. During SBNW testing, 0.51 oxygen boluses were inhaled from three different lung volumes: functional residual capacity (FRC), 11 above FRC and near total lung capacity (TLC). Following inhalation of the oxygen bolus subjects exhaled to residual volume and then inhaled to TLC. During FOT, subjects breathed 0.5-1.01 tidal volumes but with gradually increasing end-expiratory lung volume until close to TLC, then returned to normal breathing before inhaling to TLC. This was also repeated but with reducing lung volume from TLC. Absolute lung volumes were measured by body plethysmography and related to volumes during FOT and SBNW by reference to TLC obtained at the end of each SBNW or FOT test manoeuvre. Distensibility was calculated as the linear regression slopes of VDF or Grs versus lung volume. Distensibility measured by VDF ranged 16-37 ml 1(-1) lung volume and by Grs it ranged 0.06-0.19 1 s(-1) cmH2O(-1) 1(-1) lung volume. Both distensibility measurements were correlated (Pearsons R2 = 0.91, p = 0.001). The SBNW and FOT are comparable methods for measuring airway distensibility and may have similar clinical usefulness. However, further studies are required to make any specific inferences about the relationship between airway distensibility by FOT and airway remodelling.